Traditional vaccine modalities have unfortunately failed against HIV, due in part to the enormous sequence diversity of the virus. Therefore, a novel vaccine approach, which circumvents the obstacle of viral diversity, is desperately needed. Endogenous retroviruses (ERVs) are the genetic fossil remains of ancient exogenous retroviral infections present in the genome of all mammals. While the majority of ERVs are lethally mutated, some retain protein- coding capacity. We have identified ERV-specific T cell responses in a simian immunodeficiency virus (SIVmac239)-infected Indian rhesus macaque. These ERV-specific T cells recognize SIV-infected cells in vitro. We hypothesize that SIV-infection triggers ERV activation and that ERV-specific T cells recognize and eliminate SIV-infected cells, thereby contributing to containment of viral replication. Here we propose a series of experiments to test this hypothesis and lay the foundation for testing a vaccine, which targets ERVs as a surrogate marker of SIV infection. In Specific Aim 1: We will determine if ERV-specific T cells are common in SIV infection. We will define ERV-specific T cell responses against conserved ERV open reading frames (ORFs) in our cohort of SIV-infected rhesus macaques. We will use peptide sets of 15-mers overlapping by 11 corresponding to ERV ORFs with protein coding capacity. In Specific Aim 2: We will measure the ability of ERV-specific T cells to suppress viral replication. We will measure how effectively ERV-specific CD8+ and CD4+ T cells kill virally infected cells in vitro. We expect SIV infection to activate ERV replication and that ERV-specific T cells will suppress viral replication in vitro. This research will establish the foundation for studying the safety and efficacy of an ERV-based T cell vaccine by providing defined T cell epitopes to monitor in future vaccine studies. This approach circumvents the obstacle posed by the large sequence diversity of HIV. PUBLIC HEALTH RELEVANCE: The sequence diversity of HIV is a major stumbling block to the development of an effective vaccine. Here, we propose the first step of targeting endogenous retroviruses (ERV) as means to circumvent the obstacle posed by the sequence diversity of HIV. To this end, we hope to identify ERV-specific immune responses in SIV- infected rhesus macaques.